2-hydroxy-5,2&#39;-dichloro-4&#39;-nitrobenzanilide for combating tapeworms



3,974,848 2=HYBRXY-5,Z'JDHCHLURlP- i'-NlTRBENZ- ANlLlL'E Fill-R CilMZdATlNG TAPEWQFMS Rudolf Giinnert, and ErnstSchraufstatter, Wnppertal- Elberfeld, Germany, assignors to Farhenfahrilren Bayer Alrtiengesellsehaft, Leverirusen, Germany, a corporation of Germany No Drawing. Filed duly 13, 1960, Ser. No. 43,238

ilairns priority, application Germany Feb. 2, 1960 3 Claims. (Ci. 165 655) Tapeworm infections in man as well as in pets and in domestic animals play an important part in many countries. Thus, according to estimates by Stoll, about 72,000,000 men are said to have been infected by tapeworms in 1947.

The most important human tapeworms are the bovine tapeworm Taenia saginam, the wide fish tapeworm Diplzylloborhrium latzrm, and the dwarf tapeworm Hymanolepz's norm. Compared with these, the very dangerous swine tapeworm of man, Taenia soluim, plays a relatively lesser role, since only about 3,000,000 men are infected with this parasite. In View of the damage caused by tapeworms to their hosts (man and animal), treatment of the infections is absolutely essential also from the medical point of view. However, owing to the frequent deterioration in the state of the patents health, therapy for tapeworm with most of the therapeutic agents at present available represents a very intense strain, and therefore the remedy must often be eifected by stationary treatment in a hospital. Relevant dietetic preparations and the necessity for subsequent administration of a laxative are the most important tapeworm agents in order to avoid toxic effects and to ensure success of therapy, and constitute a further strain on the patient.

Apart from the agents originating from popular medicine, e.g. pelletierine from pomegranate bark, fiores koso, kamala, and pumpkin seeds, whose efiicacy is altogether unsatisfactory and which therefore only possess historical significance, mention must be made, as the most important medicines, of extracts from male fern (extractum filix mas), am-inoacridine derivatives, and in some tropical regions carbon tetrachloride. In comparison with these, tetrachloroethylene and hexylresorcinol play a minor role as tapeworm agents in human medicine.

The filix extract with the two most important active ingredients filamarone and filicine must be regarded as a relatively toxic drug. Extractum filicis is usually administered rafter preliminary fasting in capsules at maximum dosage rates of 8 cc. to an adult within half an hour. After about an hour, he is purged throughly with a saline laxative in order to prevent toxic manifestations. The success of this treatment and the tolerance for the agent are by no means always satisfactory. Moreover, a series of contra-indications are opposed to its application.

The acridine derivatives are administered at a total dose of up to 0.8 g. active substance to the adult on an empty stomach, in the form of tablets within half an hour or with the aid of the duodenal probe. After further two hours, it is necessary to administer a saline laxative with drastic activity. Relevant therapeutic preparations are also required for this therapy, during which temporary side-efiects must be expected and which is not indicated in every case. Its efficacy is usually somewhat superior to that of filix extract.

in some tropical regions, carbon tetrachloride is more frequently applied as tapeworm agent, and regarded as quite a good agent. However, the risk of damage to the liver always exists with this chemical.

in very recent times, tin and tin salts have regained their importance in human medicine. The treatment of human tapeworm infection does not require any special preparation, and the application of a laxative is not required. Tolerance is good, and the success is usually satisfactory. However, it is a disadvantage during therapy with tin preparations that it is necessary to administer the agent three times daily during three to five days.

Apart from these preparations predominantly for human medicine, there exists an entire series of preparations applied in veterinary medicine, although these are also not fully satisfactory.

it is therefore of importance to develop a novel tapeworm agent whose administration is possible without major dietetic preparation and application of laxatives, which does not exhibit any toxic side-effects, and which can be applied in human as well as in veterinary medicine owing to its effect on different types of tapeworm. The development work was mainly carried out on the experimental Hymenolepis diminuta infection of the rat.

During this work, active representatives were found in the benzan-il-ide series, and one of these, 2-hydroxy-5,2- dichloro-4-nitrobenzanilide, was selected for wider investigation. The compound is a light-grey-yellow pow .der without taste and smell, soluble in water with diffi- ,culty, which exhibits an excel-lent tolerance during the extensive pharmacological-toxicological animal experiments as well as during clinical application. T oxicological: On single oral application, mice tolerated 2 g./kg. without showing symptoms of any kind, larger doses were not tested. An administration of 1 g/kg. was tolerated by rabbits without symptoms, after 2.5 g./kg. and 5 g./kg., rapidly passing disorders were indicated. Cats did not react to single doses up to 0.5 g./kg.; after 1 g./l;g., one of the animals was caused to vomit but suffered no lasting damage.

Even when administered orally several times, the preparation was satisfactorily tolerated by the experimental animals. Rats received orally 1 g./kg. per day for 12 days without any influence on their good state of health. Rabbits tolerated a dose of 0.1 g./kg. for 12 days. Larger doses were not tested.

On local application of the moistened powder by placing it on the slain, no irritations were caused either on a rabbit or on a human being. Chemotherapeutical: (a) Rats experimentally infected with the rat tapeworm Hymenolepz's diminzaa are treated with various doses of 2- hydroxy-S,2-dichloro-4-nitro-bcnzanilide as soon as the worms have attained sexual maturity and eluminate the tapeworm eggs in the droppings. To control the efiicacy, the droppings are examined for tapeworm eggs during and after treatment. If elimination of tapeworm eggs ceases during treatment, the experimental animals are killed after a subsequent period of observation, and the intestine is investigated macroscopically and microscopically for tapeworms and the heads of tapeworms. Under these experimental conditions, the following results were obtained:

Oral treatment on five successive days with the single dose stated in each case:

1 g./ltg.--Cure 0.25 g./kg.-Cure 6.1 g./kg.Cure

6.05 g./ltg.Partia1 cure (after this dose, a larger number of tapeworms was found on dissection only in one of 13 rats) Single oral administration:

1 g./kg.Cure 0.5 g./kg.Cure 0.25 g./kg.Cure

0.1 g./kg.-Partial cure (recidivist egg elimination, then only individual parasites on dissection) 0.05 g./l g.-Partial cure (at this dose, the average number of parasites per rat was reduced by about 50% in comparison with the controls) At lower closes, the therapeutic eiiect was correspondingly lower.

([2) Experiments with the mouse tapeworm Hymenolepz's nana fraterna which is closely related to the drawf tapeworm in man hymenolepis nana:

0.5 g./l .g.Cure 0.25 g./kg.Cure 0.1 g./kg.Partial cure 0.05 g./kg.-iartial cure (c) Parasites important in veterinary medicine: 2-hydroxy-S,2'-dichloro-4'-nitrobenzanilide proved efiective towards the two canine tapeworms Taenia Izydatigeiza and Dipylidium canz'um at various dosage rates down to the lowest dose of 0.05 g./l g. so far applied.

For a head of cattle, several sheep, and a goat which were infected with Moniezia expansa, a cure could also be effected with the novel tapeworm agent down to the lowest dose of 0.05 g./ kg. so far applied, as confirmed by investigation of the droppings and usually from evidence on dissection.

(11) Human tapeworm infections: The results so far obtained for the clinical test of Z-hydroxy-S,2-dichloro- 4-nitrobenzanilide on persons of various ages suffering from the bovine tapeworm of man, Taenia saginata, show that for this infection, the novel tapeworm agent is also very effective with the best tolerance. In all the cases so far treated (more than 30), it is reported that there is very good tolerance for the total dose of 2 g./ adult. The dose was first administered as two single doses at an interval of about 12 hours, later as two single doses at an interval of one hour. According to the present experiences, no special preparations are required for therapy. Administration of a laxative is not necessary from the point of view of efiiciency and of avoidance of toxic sideettects. However, it is easier to establish the success of therapy by adminstering a laxative a few hours after treatment so as to discharge the tapeworm. During the three months period of subsequent observation required to confirm the results of therapy, there has so far been no report that a relapse has occurred in any case.

Consequently, one to two single doses of one gram are sufficient to kill a tapeworm in man. In that case, the active material can be administered in the form of tablets, pills, as powder, or in suspension. For this purpose, the active material is processed in the usual manner with suitable carrier substances.

Example 1 500 g. 2-hydroxy-S,2'-dichloro-4-nitrobenzanilide are mixed well with 130 g. maize starch, 18 g. talcum, and 2 g. magnesium stearate, and pressed into tablets with 0.5 g. active material.

Example 2 100 g. 2-hydroxy-5,2'-dichloro-4-nitrobenzanilide, 10 g. bentonite, 12 g. CMC medium, 1 g. Solbrol N are processed to give 1 litre of suspension with a 30% sugar syrup and an aroma agent. This contains 0.5 g. active agent in 5 cc. (:1 teaspoon).

We claim:

1. A process for combating tapeworm infections in warm-blooded animals, that comprises administering to the afflicted host an efiective quantity of 2-hydroxy-5,2- dichloro-4'-nitrobenzanilide.

2. An oral composition in unit dosage form for combatting tapeworms in warm-blooded animals, that comprises a significant quantity of a chemotherapeutic carrier and from 0.0250.5 gram per kilogram of body weight of 2-l1ydroxy-5,2'-dichloro-4-nitrobenzanilide.

3. An oral composition in unit dosage form for combatting tapeworms in warm-blooded animals, that comprises a significant quantity of a chemotherapeutic carrier and from 0.0'3-05 gram per kilogram of body weight of 2-hydroxy-5,2-dichloro-4-nitrobenzanilide.

References Cited in the file of this patent FOREIGN PATENTS 1,024,745 Germany Feb. 20, 1958 OTHER REFERENCES Chem. Abst., vol. 54, page 25547(s), 1960, citing German Patent 1,024,745 and British Patent 824,345. 

1. A PROCESS FFOR COMBATING TAPEWORM INFECTIONS IN WARM-BLOODED ANIMALS, THAT COMPRISES ADMINISTERING TO THE AFFICTED HOST AN EFFECTIVE QUANTITY OF 3-HYDROXY-5,2''DICHLORO-4''-NITROBENZANILIDE. 